Efficient synthetic inhibitors of anthrax lethal factor

Martino Forino, Sherida Johnson, Thiang Y. Wong, Dmitri Rozanov, Alexei Y. Savinov, Wei Li, Roberto Fattorusso, Barbara Becattini, Andrew J. Orry, Dawoon Jung, Ruben A. Abagyan, Jeffrey W. Smith, Ken Alibek, Robert C. Liddington, Alex Y. Strongin, Maurizio Pellecchia

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

Inhalation anthrax is a deadly disease for which there is currently no effective treatment. Bacillus anthracis lethal factor (LF) metalloproteinase is an integral component of the tripartite anthrax lethal toxin that is essential for the onset and progression of anthrax. We report here on a fragment-based approach that allowed us to develop inhibitors of LF. The small-molecule inhibitors we have designed, synthesized, and tested are highly potent and selective against LF in both in vitro tests and cell-based assays. These inhibitors do not affect the prototype human metalloproteinases that are structurally similar to LF. Initial in vivo evaluation of postexposure efficacy of our inhibitors combined with antibiotic ciprofloxican against B. anthracis resulted in significant protection. Our data strongly indicate that the scaffold of inhibitors we have identified is the foundation for the development of novel, safe, and effective emergency therapy of postexposure inhalation anthrax.

Original languageEnglish (US)
Pages (from-to)9499-9504
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number27
DOIs
Publication statusPublished - Jul 5 2005
Externally publishedYes

    Fingerprint

Keywords

  • Drug design
  • Fragment-based design
  • Metalloprotease
  • NMR
  • Protective antigen

ASJC Scopus subject areas

  • Genetics
  • General

Cite this